Is ERCC2 p.Arg683Gln (c.2048G>A) pathogenic?

ERCC2 p.Arg683Gln (c.2048G>A) is classified Pathogenic in ERCC2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.9978); Ultra-rare (popmax 0.0164%, mid); Associated with trichothiodystrophy 1, photosensitive.

What condition is associated with ERCC2 p.Arg683Gln (c.2048G>A)?

ERCC2 p.Arg683Gln (c.2048G>A) is associated with trichothiodystrophy 1, photosensitive, inflammatory bowel disease 1, xeroderma pigmentosum group D (ClinVar).

How common is ERCC2 p.Arg683Gln (c.2048G>A) in the general population?

ERCC2 p.Arg683Gln (c.2048G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ERCC2 p.Arg683Gln (c.2048G>A)?

AlphaMissense predicts likely pathogenic (score 0.9978) — an in-silico prediction, not a clinical call.

ERCC2 p.Arg683Gln

c.2048G>A · rs758439420 · VCV264679

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9978 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

trichothiodystrophy 1, photosensitive

Computational evidence

Protein change
AlphaMissense	0.9978	likely pathogenic ✓ concordant with ClinVar · top 8% in ERCC2
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -13.71	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.98	acceptor gain · deltas
Pangolin	Δ0.60	gain · loss 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00136% 22/1,613,776 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
South Asian	0.00768%	13,013
East Asian	0.00446%	22,446
African / African-American	0.004%	24,974
Admixed American	0.00167%	59,992
European (non-Finnish)	0.000678%	147,492

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ERCC2
Protein: p.Arg683Gln
Coding: c.2048G>A
MANE Select: NM_000400
dbSNP: rs758439420
Type: single nucleotide variant
Location: chr19:45352351 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.74 · 55 PDB
Residue 683: an α-helix; a UniProt-annotated variant site (in xp-d); a UniProt-annotated variant site (in xp-d; vitamin d-mediated activation of cyp24a1 is impaired in patient fibroblasts due to altered tfiih-dependent phosphorylation of ets1, subsequent impaired cooperation of ets1 with vdr and altered vdr recruitment to cyp24a1 promoter; damaged dna opening by tfiih is impeded)

Full ERCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

trichothiodystrophy 1, photosensitive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: inflammatory bowel disease 1 xeroderma pigmentosum group D cerebrooculofacioskeletal syndrome 2

Similar variants

ERCC2 p.Arg683Trp Pathogenic/Likely pathogenic ★★ same residue
ERCC2 p.Arg683= Likely benign ★★ same residue
ERCC2 c.1238-1G>C Likely pathogenic ★★ same condition
ERCC2 c.1308-2A>G Likely pathogenic ★★ same condition
ERCC2 c.1378-1G>T Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1479+2T>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1480-1G>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1480-2A>C Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ercc2-p-arg683gln (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown